HIV-1 entry is a critical step early in the virus life cycle. Inhibition of HIV-1 entry will prevent the virus from entering the cells. Even though the viral entry is an attractive target for drug design, there is no FDA approved anti-entry drug available. Many HIV-1 entry inhibitors are currently under preclinical studies. Betulinic acid derivatives, such as IC9564 and RPR103611, are a class of entry inhibitors that specifically interact with HIV-1 envelope glycoproteins. Although betulinic acid derivatives can inhibit a broad spectrum of HIV-1 isolates, they are less potent and more toxic than most of the clinic anti-HIV drugs such as AZT. Thus, the objective of this study is to synthesize betulinic acid derivatives as anti-HIV entry agents with a superior pharmacological profile. This is a step toward our long-term goal to develop an effective anti-HIV-1 entry inhibitor. The betulinic derivatives can be structurally divided into two moieties: A long aliphatic side chain and a betulin nucleus. The central hypothesis is that the aliphatic side chain at C-28 of the betulinic acid derivative is the primary pharmacophore for their anti-HIV-1 entry activity; while the betulin triterepene moiety provides a molecular scaffold facilitating the anti-entry and is associated with the unwanted cytotoxicity. Modifications in these two moieties are expected to alter their pharmacological profiles. The objective will be achieved and the hypothesis will be tested by pursuing the following aims: 1) Design and synthesize BA derivatives with increased water solubility, potency and reduced toxicity through modification of C-28 side chain. Three classes of peptide-conjugated BA derivatives will be synthesized. 2) Modify the betulin moiety by replacing it with structurally similar triterpenes. Hopefully this investigation will eventually lead to the discovery of non-triterpene molecular scaffolds. 3) Determine the anti-fusion potency and anti-viral spectrum of the new BA compounds. This aim is also set to explore their pre-clinical potentials including examining their toxicity. A betulinic acid derivative with potent anti-HIV entry activity has potential to become a valuable addition to current AIDS therapy.